Nakashima E, Ishizaki J, Takeda M, Matsushita R, Yokogawa K, Ichimura F
Hospital Pharmacy, Kanazawa University, Japan.
Biopharm Drug Dispos. 1993 Nov;14(8):673-84. doi: 10.1002/bdd.2510140804.
We studied the effects of experimental diabetes on the pharmacokinetics of biperiden (BP) and scopolamine (SP) and brain muscarinic receptor alterations in rats after the injection of streptozotocin (STZ) (60 mg kg-1 i.v.). The serum levels of BP and SP differed significantly between the rats 14 weeks after the STZ treatment and age-matched control rats. The values of total body clearance (CLtot) of BP and SP were significantly increased by STZ treatment. The values of volume of distribution (Vdss) of SP were slightly increased in the STZ-treated rats, although Vdss of BP was decreased. Because of the high lipophilicity of BP, Vdss of BP may be decreased due to the reduced fat tissue volume caused by STZ treatment. The density of the muscarinic receptors in whole brain was measured by a radioligand receptor binding assay using [3H]-quinuclidinyl-benzylate ([3H]-QNB). The density in the diabetic rats two weeks after the STZ treatment was significantly decreased compared to age-matched control rats. However in the diabetic rats 14 weeks after the STZ treatment, there was no difference in the density of muscarinic receptors. The IC50 of muscarinic antagonist for the binding of [3H]-QNB to the receptor did not change on STZ treatment. Modulation of the receptor following repeated anticholinergic drug exposure was studied. In control rats, the number of muscarinic receptors in the brain increased by 6.9% on chronic treatment with BP for two weeks. When diabetic rats were treated with BP and SP, the number of muscarinic receptors in the brain increased by 9.6% and 33.8%, respectively.
我们研究了实验性糖尿病对大鼠注射链脲佐菌素（STZ，60mg/kg静脉注射）后比哌立登（BP）和东莨菪碱（SP）药代动力学以及脑毒蕈碱受体改变的影响。STZ治疗14周后的大鼠与年龄匹配的对照大鼠相比，BP和SP的血清水平有显著差异。STZ治疗使BP和SP的总体清除率（CLtot）值显著增加。STZ治疗的大鼠中SP的分布容积（Vdss）值略有增加，而BP的Vdss降低。由于BP的高亲脂性，STZ治疗导致脂肪组织体积减少，可能使BP的Vdss降低。使用[3H]-喹核醇基苄酯（[3H]-QNB）通过放射性配体受体结合试验测量全脑毒蕈碱受体的密度。与年龄匹配的对照大鼠相比，STZ治疗两周后的糖尿病大鼠的密度显著降低。然而，STZ治疗14周后的糖尿病大鼠，毒蕈碱受体密度没有差异。毒蕈碱拮抗剂与[3H]-QNB结合受体的IC50在STZ治疗后没有变化。研究了反复给予抗胆碱能药物后受体的调节情况。在对照大鼠中，用BP慢性治疗两周后，脑中毒蕈碱受体数量增加了6.9%。当糖尿病大鼠用BP和SP治疗时，脑中毒蕈碱受体数量分别增加了9.6%和33.8%。
